Alcohols in direct carbon-carbon and carbon-heteroatom bond-forming reactions: recent advances

In recent years, nucleophilic substitution of alcohols leading to the formation of the C-C and C-heteroatom bonds has become an attractive process used in the synthesis of organic compounds, offering a potential impact on the environment


Introduction
The development of protocols for the transformation of organic compounds following the principles of green chemistry 1 is currently one of the main trends in organic synthesis.The achievement of atom economy, efficient catalytic methodologies, suitability of a safer reaction media (water, ionic liquids, fluorous liquids, etc.) or solvent-free reaction conditions (SFRC) instead of the volatility of organic solvents, low energy consumption and low waste residues are major challenges in organic synthesis.
Hydroxyl functional group is one of the most abundant in organic compounds; thus, hydroxyl group transformations under green reaction conditions represent a considerable challenge and have attracted the interest of organic chemists.
3][4] Numerous related methodologies have been elaborated using a substoichiometric amount of Brønsted acid, Lewis acid, molecular iodine or other promoter.
Recently, the synthesis of 4H-chromenes from o-hydroxybenzylic alcohols and various diketones / ketoesters / ketoamides in the presence of sodium bisulfate on silicagel in DCE was reported 9 (Scheme 2) whereas, Fe(HSO 4 ) 3 -catalysed C-alkylation of a variety of β-dicarbonyl compounds (acyclic and cyclic βdiketones, β-keto esters and β-diester) using benzylic and allylic alcohols as electrophiles in 1,2-dichloroethane was developed.The catalyst can be recovered and reused up to five times. 10Scheme 2. Reactions of 2-(hydroxy(phenyl)methyl)phenol 4 with dicarbonyl compounds catalyzed by NaHSO 4 -SiO 2 .Dodecylbenzenesulfonic acid (DBSA) has been used as surfactant-type Brønsted acid catalyst for the dehydrative nucleophile substitution of benzyl alcohols with various arenes/hetroarenes in water, whereas, common Brønsted acids such as AcOH, TfOH, TFA and TsOH were not found to be effective.Moreover, DBSA has been used for the stereoselective C-glycosylation of hydroxy sugars (Scheme 3). 11Scheme 3. Dehydrative nucleophilic substitutions of alcohols in water catalyzed by DBSA.
In addition recent approaches for direct dehydrative coupling strategies to form C-C bond in the presence of Brønsted acid as a catalyst have been reviewed 29 and selected results are presented below in Table 1.It is known that the use of sodium hydrogen sulfate supported on silica allows alkylation of aromatics with alcohols.After screening of various acid catalysts at 80 o C, 2 h, it was found that silica sulfuric acid (SSA) catalyzed the reaction between diphenylmethanol and benzene in 83% yield.When the reaction was performed in the presence of NaHSO 4 no reaction was observed.Gel-supported acids PPA/SiO 2 and SA/SiO 2 catalysed the reaction to some extent and the corresponding products were obtained in low yields (13-22%); ZnCl 2 /SiO 2 gave the corresponding product in 70% yield.In the cases when Lewis and Brønsted acids (AlCl 3 , FeCl 3 , H 2 SO 4 ) were used, the corresponding products were obtained in 32-76% yields.Different aromatic compounds were treated with benzhydrol catalyzed by NaHSO 4 /SiO 2 , in DCE (Scheme 4).The catalyst can be recycled and reused eight times without losing its activity. 32cheme 4. Alkylation of aromatics from alcohols in the presence of NaHSO 4 /SiO 2 as the catalyst.
Direct allylation of alcohols 33,34 using allyltrimethylsilane for C-C bond formation as well as nucleophilic substitution of propargyl alcohols with various nucleophiles (NuH = C, N, O, S, I) in the presence of Brønsted acid as catalyst have been reviewed 35,36 and selected results are shown in Table 2 35 and in Scheme 5 26 respectively.Furthermore, the Ritter reaction is a very efficient and widely used protocol for the formation of amides.Remarkable progress has been made and developments in the Ritter reaction in the presence of Brønsted acid as a catalyst were reviewed in 2012. 42In 2006, Hu et al. reported the Ritter reaction of tertiary α-CF 2 H carbinols with acetonitrile in the presence of 98% concentrated H 2 SO 4 to provide the corresponding amides in high yields. 19arlier, in 2002, Sanz et al. reported the amidation of secondary alcohols in high yields using a Brønsted acidcatalyst (Table 3). 43The amidation of 1-phenylethanol was performed using different Brønsted acids as catalysts (10 mol%) such as PTSA, 2,4-dinitrobenzenesulfonic acid (DNBSA), TfOH and H 2 SO 4 in acetonitrile.The only difference between these acids was the reaction time required for conversion of the starting material.Due to its high activity and ease of handling, DNBSA (10 mol%) was used as catalyst for this reaction.When the substoichiometric amount of DNBSA was decreased from 10 mol% to 5 mol% the reaction time was increased from 12 h to 24 h for the formation of the main product.Recent developments in the Ritter reaction of alcohols [45][46][47][48][49] and nitriles catalyzed by Brønsted acids have been reviewed; 50 and some of the results are shown in Table 4.
A convenient and efficient method for C-C bond formation was developed by direct dehydrative coupling of alcohols or alkenes with alcohols using a series of alkanesulfonic acid group-functionalized ionic liquids (SO 3 H-functionalization IL) without additives in DCM.The protocol provides the ability for the synthesisof polysubstituted olefins in good to excellent yield.Sanz et al. reported the direct nucleophilic substitution of the allylic and benzylic alcohols with different nucleophiles using p-toluenesulfonic acid monohydrate (PTSA) or polymer-bound p-toluenesulfonic acid (5 mol%) where water was the only side product (Scheme 6). 13Scheme 6. Substitution reactions of alcohol with different nucleophiles catalyzed by PTSA.
Direct nucleophilic substitutions of the propargylic alcohols with a large variety of carbon-and heteroatom-centered nucleophiles have been also reported by Sanz's group.After screening of various Brønsted acids (5 mol%), also Lewis acids such as InCl 3 , AlCl 3 and CeCl 3 , were shown to catalyse the reaction between an alkynol and ethanol as nucleophiles in MeCN, at 80 o C, producing the corresponding product in >95%, 80% and 34% yields in 1-36 h.The same reaction was catalysed by PTSA or CSA and the corresponding products were obtained in quantitative yields.Moreover, dilute HCl (10 mol%) also catalysed this reaction in excellent yield. 14ater, Sanz's group performed a direct alkylation reaction between indoles and tertiary propargylic alcohols catalysed by p-toluenesulfonic acid (PTSA, 5 mol%), in MeCN, at room temperature. 15lkylation of furans by benzyl and propargyl alcohols 14,16 in the presence of Brønsted acids as catalyst have attracted the interest of the researchers 17 and selected results are shown in Table 5.Furthermore, the catalytic nucleophilic substitution of tertiary alcohols 11,18,19 using carbon-or heteroatombased nucleophiles in the presence of Brønsted acid has been reviewed 20 and selected results are shown in Table 6.In 2013 Zheng's group developed the method for the direct nucleophilic substitution of propargylic alcohols with various nucleophiles using Amberlite IR-120H resin as the catalyst. 21he direct nucleophilic substitution of allylic alcohols [22][23][24] through S N 1-type reactions in the presence of Brønsted acid as a catalyst has been reviewed, 25  Moreover, the direct nucleophilic S N 1-type reactions of alkynols 26,27 in the presence of Brønsted acid as a catalyst have been reviewed 28 and selected results are shown in Table 8.In 2016 six Brønsted acid-type amphiphilic calix[n]arene derivatives were used as catalysts in a coupling reaction of 2-methylfuran and/or N-methylindole with some sec-alcohols in aqueous media 37 whereas, Sanz's group reported an efficient protocol for the synthesis of fused polycyclic indoles by intramolecular alkylation of indoles with alcohols by employing a simple Brønsted acid (PTSA) as a catalyst in MeCN. 40nterestingly, triflic acid and trimethyl orthoformate in CCl 4 , promoted direct α-alkylation of unactivated ketones using benzylic alcohols as electrophiles via in situ formed acetals. 38In 2015 Bhanage et al. developed an efficient method for the synthesis of substituted aryl ketones by employing Amberlyst-15 immobilized in [Bmim][PF 6 ] ionic liquid as a recyclable catalytic system which was recycled up to five times without losing the catalytic activity. 39In 2016 also, Bolshan et al. described an efficient methodology for the allylation of benzhydryl alcohols using allyltrimethylsilane in the presence of tetrafluoroboric acid (HBF 4 •OEt 2 ) as catalyst in DCE. 41n 2011, Laali et al. reported Brønsted-acidic imidazolium ionic liquid [BMIM(SO 3 H)][OTf] as a convenient and recyclable catalyst for the high yield synthesis of variety of amides under mild conditions via the Ritter reaction of alcohols with nitriles. 44Moreover, use of NOPF 6 immobilized in [BMIM][PF 6 ] ionic liquid for the Ritter reaction of bromides with nitriles and for the oxidative Ritter-type synthesis of adamantyl amides from adamantane and nitriles.
Moreover, unsymmetrical ethers were prepared from different alcohols in the presence of sodium bisulfite (NaHSO 3 , 0.3-1 mol%) as the catalyst. 51n 2012 Gowda et al. performed an efficient synthesis of tert-butyl ethers from alcohols using methyl tertbutyl ethers as a tert-butyl source and solvent, in the presence of H 2 SO 4 . 52Synthesis of several diphenylmethyl ethers and thioethers was achieved using a combination of microwave irradiation and protic ionic liquids (pIL), namely triethylaminomethanesulfonic acid (TeaMs) as a co-solvent and catalyst in an organic solvent (Scheme 7). 53heme 7. Formation of diphenylmethyl ether 25 using protic ionic liquids.
Later, in 2015, Aoyama's group has developed a simple and efficient method for the construction of chroman ring system from a combination of benzylic and aliphatic alcohols in the presence of NaHSO 4 /SiO 2 as a catalyst in DCE. 54n 2015 also phosphinic acid has been employed as catalyst for intramolecular nucleophilic substitution of the hydroxyl group of aryl, allyl, propargyl and alkyl alcohols by O-, S-, and N-centered nucleophiles to yield enantiomerically-enriched five-membered heterocyclic compounds 55 and in 2016 Samec's group reported an intramolecular nucleophilic substitution of stereogenic alcohols using phosphinic acid (H 3 PO 2 , 10 mol%) as a catalyst in DCE at 80 o C. 56

Metal-catalyzed approaches
The major contribution in transformation of alcohols has been described by the activation of alcohols through catalytic amount of metal ions as Lewis acids.
The reaction was studied with different metal salts catalysts (5 mol%) in toluene at 80 o C. InCl 3 was found to act as a catalyst for the reaction, as well as InBr 3 .When the reaction was performed in the absence of nucleophile, dimerization took place.This was then tested with acetylacetone in the presence of water giving the corresponding alkylated product (Scheme 9).The reactions of alcohols were tested also with indoles in order to give corresponding products.Scheme 9. Effect of InCl 3 on dimerization and alkylation.
Chan and co-workers developed allylic alkylation of 1,3-dicarbonyl compounds with allylic alcohols including primary and terminal ones using AuCl 3 (5 mol%) with AgSbF 6 (15 mol%) as co-catalyst, in MeNO 2 at room temperature. 59he direct allylation of alcohols catalyzed by the combined Lewis acid system of InCl 3 / Me 3 SiBr has been reported.This system was tested for the direct allylation between tertiary aliphatic trimethylsilyl ethers and allylsilanes but the yield was found to be only 34%.Utilizing a combination of InCl 3 / Me 3 SiI, which is a stronger Lewis acid, proved to be a better choice (61% yield) at room temperature in DCM as the solvent.Furthermore, the use of the combination of InCl 3 and I 2 , where Me 3 SiI was generated in situ from I 2 and allylsilane, enhanced the yield to 76%, while each of them separately did not shown any activity. 60shii and co-workers developed a convenient secondary benzylation and allylation of 1,3-dicarbonyl compounds in the presence of metal triflate (e.g.La, Yb, Sc, and Hf triflate, 0.5 mol%), in MeNO 2 (Scheme 10).61 Scheme 10.Benzylation of 1,3-dicarbonyl compounds catalyzed by metal triflate.Baba et al. reported a rapid and efficient microwave-irradiated protocol for C-C coupling of a broad range of benzylic/allylic alcohols with 1,3-dicarbonyl compounds, β-keto esters, and dialkyl malonates catalyzed by transition metal salts in toluene. 62Transition-metal catalysts, salts of Zn, Cu, Fe, Sc, Ru, Pt and Ta (3-5 mol%) were found to provide the coupling products (Scheme 11).Among all of these catalysts copper(II) triflate (5 mol%) has been observed to be more effective (98% yield) than the other catalysts, even in the case of a less reactive benzyl alcohol or diester.Later, Fe(III) chloride catalyst was explored for the α-substitution of Morita-Baylis-Hillman alcohols with alcohol carbon-and heteroatom-centred nucleophiles such as alcohols, arenes, 1,3-dicarbonyl compounds and thiols. 63irupathi and Kim studied the role of Fe(ClO 4 ) 3 •H 2 O as catalyst for the direct C-C bond formation of 1,3dicarbonyl compounds, electron rich arenes and heteroarenes and 4-hydroxycoumarin with secondary benzylic alcohols. 64This method was applied to the synthesis of bis-symmetrical triarylmethanes and a onestep synthesis of an anticoagulant compound, 4-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-1-yl)-2H-chromen-2-one (Coumatetralyl B).Dalla and Dunach's group developed the role of Sn(IV) triflimidate as the catalyst for the nucleophilic replacement of hydroxy groups of hydroxy N,O-acetals (Scheme 12) . 65cheme 12. Sn(IV) triflimidate catalyzed nucleophilic substitution of hydroxy N,O-acetals.
Beller and co-workers found FeCl 3 •6H 2 O to be an inexpensive catalyst for the addition of various 1,3dicarbonyl compounds with benzylic alcohols in MeNO 2 . 66The protocol was useful in a one-pot synthesis of the pharmaceutical drug Phenprocoumon in 94% yield.
Aridoss and Laali reported the condensation of propargylic alcohols with 1,3-dicarbonyl compounds in the presence of Sc(OTf) 3 and Ln(OTf) 3 and bismuth nitrate in imidazolium ILs.The [BMIM][PF 6 ]/Bi(NO 3 ) 3 •5H 2 O system was efficient for propargylation, vinylation, and alkylation of 4-hydroxycoumarins. 67i(OTf) 3 (1 mol%) catalyzed benzylation and allylic alkylation of 2,4-pentanediones in MeNO 2 forming C-C bond in good to excellent yields. 68bCl 5 , a stable solid, was used as an efficient catalyst (5 mol%) for C, N, O and S-nucleophilic substitution reactions of benzylic alcohols with alcohols, naphthols, indoles, resorcinols, anisole, thiols, NH 4 SCN or NaN 3 as a source of nucleophiles.Benzylic alcohols with electron withdrawing groups such as fluoro or nitro were not reactive. 69lkylation of indoles using allylic, benzylic and propargylic alcohols catalyzed by FeCl 3 in MeNO 2 were reported by Jana et al. 70 Later, Jana et al. also described the addition of benzylic alcohols to terminal aryl alkynes catalyzed by FeCl 3 in MeNO 2 . 71In the same year, Jana et.al performed the amidation of secondary benzylic and allylic alcohols with carboxamides or p-toluenesulfonamide in the presence of FeCl 3 . 72amamoto's group developed dehydrative coupling of benzylic alcohols with styrenes catalyzed by Pd(II) using PPh 3 as the ligand and (CF 3 CO) 2 O as an additive. 73n 2011 Yi's group reported a C-C bond formation between alkenes and alcohols.The cationic ruthenium complex [(C 6 H 6 )(PCy 3 )(CO)RuH] + BF 4 --catalyzed the alkylation in solution. 74he allylic alkylation represents an important transformation in organic chemistry and different metal processes have been described for this reaction.Direct allylation of alcohols [75][76][77][78][79][80][81][82][83] using allyltrimethylsilane for C-C bond formation in the presence of Lewis acid as a catalyst has attracted the interest of the researchers 35 and some results are shown in Table 9. Heterobimetallic 'Pd-Sn' catalyst was used for the direct alkylation of arenes, heteroarenes, 1,3dicarbonyls and organosilicon nucleophiles with allylic / propargylic / benzylic alcohols in MeNO 2 . 84lkylation of electron-rich arenes using secondary and tertiary benzylic, allylic, and propargylic alcohols in the presence of calcium-based catalyst was described by Niggemann and Meel. 85Reactions were performed under the optimized conditions (5 mol% Ca(NTf 2 ) 2 and 5 mol% Bu 4 NPF 6 , in DCM, at room temperature).
A general and selective C-3 alkylation of indoles with primary alcohols in o-xylene catalyzed by reusable alumina-supported Pt nanocluster (Pt/θ-Al 2 O 3 -1.5 nm, 1 mol%) was reported. 86ransition metals could catalyze a various transformations of allylic alcohols [87][88][89][90][91] with various nucleophiles, Table 10.The review covers both C-C and C-heteroatom bond formation. 92urthermore, alkylation of furans by benzyl, allyl, and propargyl alcohols 80,[93][94][95][96] in the presence of Lewis acids as a catalyst has been also reviewed 17 and of the many results a selection is shown in Table 11.(20 mol%) in MeNO 2 at room temperature. 97he catalytic nucleophilic substitution of tertiary alcohols of type 15, using carbon or heteroatom based nucleophiles in the presence of Lewis acid has been the several publications 79,85,98,99 as well as a review 20 and selected results are shown in Table 12.
54 99 The direct nucleophilic substitution of allylic alcohols 100-103 as well as of tert-alcohols 57,104,105 through S N 1type reactions in the presence of Lewis acid as a catalyst have been reviewed 25,28 and selected results are shown in Tables 13 and 14 respectively.Recent approaches for direct dehydrative coupling strategies to form C-C bond in the presence of Lewis acid as a catalyst has been reviewed 29 and selected results are shown in Table 15.Fe(HSO 4 ) 3 as a reusable catalyst was used for C-alkylation of a variety of β-dicarbonyl compounds using benzylic and allylic alcohols as electrophiles in 1,2-DCE. 106A method for the synthesis of 1,3-diarylindenes from propargylic alcohols containing aromatic ring in the presence of AuBr 3 (5 mol%) in CF 3 CH 2 OH under reflux was described. 107Rezgui's group developed a method for C-C bond formation from β-dicarbonyl compounds with both cyclic and acyclic Morita-Baylis-Hillman (MBH) alcohols using Et 3 B as a Lewis acid promoter in the presence of palladium catalyst. 108A new protocol for direct benzylation/allylation of malonates with alcohols via palladium catalyzed Tsuji-Trost type reactions has been described. 109ron-based imidazolium salts was used as a catalysts for the synthesis of quinolines and 2-and 4allylanilines by allylic substitution of alcohols with anilines. 110Lee's group developed indium(III) chloride to gold(I) as a catalyst in dehydrative reactions with allylic alcohols. 111rotocols for the direct catalytic dehydrative substitution of alcohols recently have been reviewed 112 and selected results are shown in (Table 16).Remarkable progress has been made, and developments in the Ritter reaction in the presence of a Lewis acid catalyst were reviewed in 2012. 42A general procedure allowing the conversion of tertiary alcohols with benzonitrile into tert-amides in the presence of Bi(OTf) 3 (20 mol%) as a catalyst (which was found to be the best compared with different metal triflates) in H 2 O at 100 °C for 17 h was developed by Barrett et al. 115 Recent developments in Ritter reaction catalyzed by Lewis acid have been reviewed. 50The procedure for the synthesis of amides from benzohydric alcohols and nitriles in the presence of trimesitylphosphane gold (I) complex-(Mes 3 P)AuCl with the NTf 2 -counter anion was reported by Hashmi. 116Reactions were performed under optimized conditions (5 mol% gold (I), 5 mol% AgNTf 2 in nitrile at 75 °C) and the products were obtained in generally moderate yields.Yaragorla et al. demonstrated the protocol using Ca(OTf) 2 (5 mol%) as a catalyst and Bu 4 NPF 6 (5 mol%) as an additive for the synthesis of various amides from tertiary, secondary and benzyl alcohols and nitriles under microwave irradiation in 15 min.in good to excellent yields. 117(Scheme 13) Selected products: Scheme 13.Ca(II) catalyzed amidation of alcohols with nitriles.
Wang and co-workers developed a convenient method for direct nucleophilic substitution of alcohols with aniline, amide, sulfonamide, 2,4-DNPH, and 1,3-dicarbonyl compounds catalyzed by zinc based ionic liquids [choline hydrochloride][ZnCl 2 ] 2 (1.5 equiv., 100 o C, 1 h), which acted also as the solvent, and the obtained yields were good to excellent. 118The authors reported that the reaction worked through the carbocation mechanism, as detected by UV-VIS spectroscopy.Matute's group developed a method for alkylation of (hetero)aromate amines with various primary alcohols in the presence of ruthenium pincer complex as a catalyst. 119he highly α-regioselective In(OTf) 3 (10 mol%) catalyzed N-nucleophilic substitution of Baylis-Hillman adducts bearing five or six-membered ring moieties with aromatic amines gave the α-product in good yield. 120 characteristic example is shown in Scheme 14. Scheme 14. Amination of a Baylis-Hillman adduct catalyzed by In(OTf) 3 .
Aluminium triflate Al(OTf) 3 has been reported to catalyze the direct amination of allylic/propargylic/benzylic alcohols, and benzhydrols with electron-withdrawing substituents, with various nitrogen nucleophiles, in MeNO 2 , to achieve the corresponding biarylamines in high yield, and the dibromosubstituted product was further converted into letrozole in high yield. 122urthermore, NiCuFeOx catalyst was designed and prepared by Shi's group for the synthesis of Nsubstituted primary, secondary, tertiary and cyclic amines (with up to 98%) using ammonia, primary amines, or secondary amines as the nitrogen source and alcohols as the alkylation reagents. 123The authors supposed that the synergism between the Ni, Cu, and Fe species might be crucial to achieve the "borrowing-hydrogen transformation".

Scheme 16. N-Alkylation of various amines with alcohols.
In 2013, N-alkylation of amines and β-alkylation of secondary alcohols with primary alcohols was achieved using a mesoporous silica (SBA-15)-supported pyrimidine-substituted N-heterocyclic carbene iridium complex as the catalyst.The catalyst could easily be recycled and re-used twelve cycles for N-alkylation of aniline with benzyl alcohol, nine cycles for N-alkylation of different amines with different alcohols, and eight cycles for β-alkylation of 1 phenylethanol with benzyl alcohol (Scheme 17). 125Scheme 17. N-Alkylation of aniline 38a with phenylmethanol 42a catalyzed by iridium.
Moreover, Niggemann et al. developed the method for direct amination of secondary and tertiary benzylic and allylic as well as tertiary propargylic alcohols with various nitrogen nucleophiles such as carbamates, tosylamides and anilines under the optimized conditions (5 mol% Ca(NTf 2 ) 2 /Bu 4 NPF 6 , in DCM, at r.t.). 126Amination of alcohols [127][128][129][130][131][132][133] in the presence of Lewis acid as a catalyst has been reviewed; 134 selected results are shown in Table 17.For the amination of allylic alcohols Pd(Xantphos)Cl 2 , was used as the catalyst. 135ong and co-workers developed a method for the direct N-benzylation of sulfonamides with primary and secondary benzyl alcohols using boron trifluoride-diethyl ether complex (BF 3 •OEt 2 ).A characteristic example is shown in Scheme 18. 136 Scheme 18. N-Benzylation of sulfonamides with benzyl alcohols.Furthermore, Cai's group reported a new tandem catalytic process for the synthesis of substituted quinolines from primary and secondary allylic alcohols with 2-aminobenzyl alcohol using [IrCp*Cl 2 ] 2 /KOH in toluene. 137A procedure for direct dehydrative amination of benzylic and allylic alcohols catalysed by cobalt(II)/TPPMS (sodium diphenylphosphinobenzene-3-sulfonate) in water has been reported. 138oyer et al. reported the procedure based on the utilization of BiBr 3 for the benzylation of aliphatic alcohols with various benzylic alcohols under mild conditions. 139amamoto and co-workers developed a simple and efficient method for the synthesis of various allylic ethers from alcohols and alkynes using a substoichiometric amount of Pd(PPh 3 ) 4 /PhCO 2 H in dioxane at 100 o C in good to high yields. 140hang et al. reported the coupling of alkynes with alcohols to give allylic ethers in the presence of palladium as a catalyst.With phenols the C-alkylation products were obtained in moderate yields (Scheme 19). 141Scheme 19.Coupling of alkyne with alcohol catalyzed by Pd(PPh 3 ) 4 .
The use of palladium complex as a catalyst for the direct preparation of symmetric and unsymmetric aromatic ethers (by coupling of two different alcohols), for the amination of secondary benzylic alcohols (with electron-deficient anilines) and for the direct formation of thioethers (by the direct action of thiols on secphenylethyl alcohol) was described by Abu-Omar. 142kariya et al. has shown the role of triphenyl phosphite-palladium complex as the catalyst for the substitution reactions of allylic alcohols via a direct C-O bond cleavage to give the corresponding allylic ethers and the related C-C and C-N bond-forming products. 143ale and co-workers developed a method for the protection of alcohols by the synthesis of diphenylmethyl ethers or bis(methoxyphenyl) methyl ethers catalyzed by PdCl 2 144 or PdCl 2 (CH 3 CN) 2 145 (Scheme 20).
Scheme 20.Formation of benzhydryl phenylethyl ether 50 in the presence of PdCl 2 catalyst.
Asensio and co-workers reported the preparation of unsymmetrical ethers from alcohols using NaAuCl 4 (2-5 mol%) as a simple gold catalyst. 146The procedure enables the etherification of benzylic and tertiary alcohols under mild conditions in moderate to good yields.
Kerton et al. reported the procedure based on the utilization of Pd(CH 3 CN) 2 Cl 2 for the etherification of benzyl alcohol in hydrophobic ionic liquids (1-Butyl-3-methylimidazolium hexafluorophosphate, [BMIM]PF 6 ) using a microwave or conventional heating. 147In the presence of NH 4 Cl chlorination of benzyl alcohol occurred.
Palladium on magnesium oxide (Pd/MgO) catalyzed the formation of thioethers from thiols and aldehydes formed in situ from the alcohol by means of a "borrowing hydrogen" method.It was noticed that in the absence of the catalyst the reaction did not occur. 148oste et al. described the role of rhenium (V)-oxo complex catalyst for the formation of C-O bond by the coupling of simple alcohols and propargyl alcohols (Scheme 21). 149heme 21.Re-oxo-catalyzed etherification of 2-methyl-4-phenylbut-3-yn-2-ol 15d.
Boron trifluoride-diethyl ether catalyzed also etherification of primary and secondary alcohols. 150e(HSO 4 ) 3 catalyzed dehydration of two different alcohols to provide unsymmetrical ether under SFRC. 151n environmentally benign protocol for S-benzylation of electron-deficient benzenethiols in water using cationic Pd (II) catalysts was reported. 152he reaction of alcohols with silanes is a widely used methodology for the transformation of a hydroxyl group into an organic molecule.The introduction of TMS group into an organic molecule is achieved using hexamethyldisilazane (HMDS) in the presence of LiClO 4 (solid) 153 or LaCl 3 154 as catalysts.
The role of InBr 3 as the catalyst was reported by Ding et al. for the direct cyanation of alcohols with TMSCN in the presence of DCM as the solvent where different benzylic alcohols could be converted to the corresponding nitriles in yields of 46-99% 155 .The reaction was studied with different Lewis acids.InCl 3 and InBr 3 turned out to be the best catalysts.In the absence of the catalyst, no reaction was observed.The authors speculated that the catalytic cycle involved some type of carbenium intermediates which were formed by the heterolytic cleavage of C-O bond of the alcohols with the assistance of Lewis acid In(III) (and TMSCN).
Chlorination of alcohols is sometimes an important transformation in organic chemistry and it has attracted significant interest over the years.A substoichiometric amount of InCl 3 in the presence of an equimolar amount of benzil, 156 or a combination of GaCl 3 (5 mol%) and diethyl tartrate (10 mol%) 157 are required for the direct chlorodehydroxylation of alcohols using HSiMe 2 Cl (Scheme 22).Scheme 22. Chlorination of propan-2-ol 1a catalyzed by InCl 3 .
The use of iron compounds as catalysts in organic synthesis has been reviewed 158 and selected results are shown in Table 18.Conversion of propargylic alcohols into various valuable products using transition-metal-catalytic systems, especially those using coinage metals (i.e.copper, silver and gold) has been reviewed, 163  Gold-catalyzed S N 1-type reaction of alcohols has been used to prepare unsymmetrical ethers and N-benzyloxycarbamate(Cbz)-protected amines. 167errocenium hexafluorophosphate ([FeCp 2 ]PF 6 ) was used as a catalyst for the etherification of propargylic alcohols at 40 o C in DCM. 168Liu's group developed addition reaction of β-diketones to secondary alcohols and styrenes to yield the αalkylated β-diketones catalyzed by perchlorate salt of the dicationic bipy-ruthenium complex cis-[Ru(6,6'-Cl 2 bipy) 2 (H 2 O) 2 ] 2+ . 170It was proposed and confirmed by independent experiments that the catalytic addition of β-diketones to the secondary alcohols was catalyzed by the Brønsted acid HClO 4 generated by the reaction of the metal complex with the ß-diketone.

Molecular iodine-catalyzed approaches
Iodine could catalyze various transformations of alcohols, which have been reviewed 171 and many results are shown in Table 20.
Benzyl 172-177 , allyl 175,178-184 and propargyl 175,185,186 alcohols 6 were treated with various nucleophiles in the presence of I 2 (2-20 mol%) and formed different types of products (Scheme 24, Table 20).Primary and secondary benzylic alcohols supplied ethers, such as 58 (R 1 = R 2 = H, R 3 = Ph), under SFRC. 187ertiary alcohols underwent elimination of water in the absence of nucleophiles providing the corresponding alkenes such as 59 (R 1 = R 2 = R 4 = H), in high yields (Scheme 24). 187iu et al. described C-C and C-N bonds formation from allylic/propargylic and other alcohols with various C-and N-nucleophiles in the presence of iodine catalyst (10 mol%) in MeCN, at room temperature. 188ereb reported an environmentally friendly synthesis of trimethylsilyl ethers from alcohols, phenols and carbohydrates in the presence of HMDS under solvent-free conditions, at room temperature.Sterically hindered phenols, carbohydrates and most of the alcohols required a substoichiometric amount of iodine (up to 2 mol%). 189as et al. reported one-spot synthesis of pentasubstituted pyrroles by the tandem reaction of amines, dialkyl acetylenedicarboxylates, and propargylic alcohols catalyzed by iodine (10 mol%), in toluene and the obtained corresponding products were in high yields (75-88%). 190

H 2 O-catalyzed approaches
Cozzi and Zoli performed the direct nucleophilic substitution of alcohol "on water" without the addition of any Brønsted/Lewis acid (Scheme 26). 192Reactions depend on the stability of the corresponding carbocation.The reactions were performed in deionized water at 80 o C. Various nucleophiles reacted smoothly with the selected alcohols.

Miscellaneous
The use of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as an efficient catalyst for direct benzylation of 1,3-dicarbonyl compounds with various benzylic alcohols in CH 3 NO 2 was described by Lalitha et al. 195 Kaneda et al. developed an environmentally benign synthetic approach to nucleophilic substitution reactions of alcohols catalyzed by proton-and metal-exchanged montmorillonites (H-and M n+ -mont).Anilines, amides, indoles 1,3-dicarbonyl compounds and allylsilane acted as a nucleophile for the H-mont-catalyzed substitutions of alcohols, for the formation of various C-N and C-C bonds.Especially, an Al 3+ -mont expressed high catalytic activity for the α-benzylation of 1,3-dicarbonyl compounds with primary alcohols (Scheme 27). 196heme 27. α-Alkylation of benzoylacetone 2d with benzyl alcohol 42a.
In 2015, Takemoto and co-workers developed a combination of a halogen bond (XB) donor with trimethyl-silyl halide (TMSX) as an efficient cocatalytic system for the direct dehydroxylative coupling reaction of alcohol with different nucleophiles bearing TMS groups, such as allyltrimethylsilane and trimethylsilylcyanide, to provide the corresponding adduct 197 whereas, in 2016 an effective method for cross-coupling of heteroaryl boronic acids with allylic alcohols under catalyst-free reaction conditions was reported. 198naka and co-workers developed a new method to transform natural montmorillonite into a solid acid catalyst employing a catalytic amount of TMSCl.The acidic montmorillonite catalyzed the azidation of benzylic and allylic alcohols with trimethylsilyazide (TMSN 3 ). 199oreover, organohalides were found as effective catalysts for dehydrative O-alkylation of different alcohols, providing homo-and cross-etherification methods for a general preparation of the useful symmetrical and unsymmetrical aliphatic ethers. 200Hypervalent [bis(trifluoroacetoxy)iodo]benzene (PhI(OCOCF 3 ) 2 , PIFA) catalyst has been found to function as Lewis acid for nucleophilic substitution reactions of propargylic alcohols with various of C-, O-, S-, and N-nucleophiles in the presence of CH 3 CN as the solvent. 201n 2012, Paquin and co-workers described chlorination/bromination (up to 92% yield) and iodination (in lower yields) of primary alcohols using a combination of tetraethylammonium halide (1.5 equiv.)and [Et 2 NSF 2 ]BF 4 (XtalFluor-E) (1.5 equiv.),2,6-lutidine, in CH 2 Cl 2 , at r.t., 12 h. 202Halogenation was limited to primary alcohols.In the case of 4-phenyl-2-butanol the halogenation was slower; as a result, fluorination became somewhat competitive (Scheme 28).Scheme 28.Halogenation of 4-phenyl-2-butanol 62.
Lambert et al. found a convenient and efficient method for converting alcohols to alkyl chlorides in excellent yields using dichlorodiphenylcyclopropene in DCM at room temperature. 203Lautens and co-workers have shown that the combination of bromotrichloromethane (CBrCl 3 ) and triphenylphosphine (PPh 3 ), in DCM at r.t., for 1 h could convert benzyl alcohols into benzyl chlorides in excellent yields. 204Qi et al. described the treatment of substituted benzyl alcohols and pyridine methanols with tosyl chloride (TsCl) and the corresponding chlorides were the main products. 205For substituted benzyl alcohols and pyridine methanols it was possible to predict whether chlorination or tosylation would occur.
Nguyen et al. developed a new method for the nucleophilic substitution of alcohols using aromatic tropylium cation activation and the chlorinated products were obtained in high yields (Scheme 29). 206cheme 29.Chlorination of 1-phenylethanol 6a.
In 2016, an efficient method for the transformation of alcohols into the corresponding alkyl iodides and bromides using KX/P 2 O 5 (X = Br, I) was reported. 207Nucleophilic substitution of alcohols catalyzed by Lewis base catalyst recently has been reviewed 208 and selected results are shown in Table 21, with the acid chlorides acting as the halide source The most recently developed method for alcohol chlorination with silanes utilizes TMSCl and natural sodium montmorillonite (Na-Mont) as the catalyst in DCM. 212In the absence of the catalyst, the efficiency of the transformation was reported to be very low (8%).The scope of this reaction is limited to secondary benzyl alcohols and strongly activated primary benzyl alcohols (Scheme 30).
Nemr and co-workers described a new method for the acetylation of cotton cellulose using acetic anhydride in the presence of NIS as a catalyst under mild reaction conditions. 213urthermore, acetylation of sugarcane bagasse with acetic anhydride under SFRC for the production of oil sorption-active materials was performed using NBS as a catalyst. 214NBS was also used for acetylation of alcohols using acetic anhydride in DCM at room temperature. 215

Conclusions
In summary, the comprehensive direct transformation of a broad range of alcohols with various sources of nucleophiles is emerging as one of the most attractive strategies from the economic and environmental point of view, producing water as a by-product of the reaction.Recent advances in this area include the activation of the hydroxyl functional group in a target molecule through the use of substoichiometric amount of Brønsted acids, Lewis acids, molecular iodine or other promoters.Still, the development of efficient, selective and environmentally benign catalytic methodologies remains an attractive research subject.We firmly believe that this review article will result in enhancing the green chemical profiles of these transformations in the future.

Acknowledgements
We are grateful to the Slovene Human Resources Development and Scholarship Fund (contract: 11011-9/2011) and the Slovenian Research Agency (contract: Programme P1-0134) for the financial support.

Table 4 .
The Ritter reaction of alcohols and nitriles catalyzed by Brønsted acid

Table 5 .
Catalytic alkylation of furan catalyzed by Brønsted acid

Table 6 .
Nucleophilic substitution of secondary and tertiary alcohols catalyzed by Brønsted acid

Table 8 .
Nucleophilic substitution of alcohol 15b catalyzed by Brønsted acid

Table 9 .
Allylation of alcohols using allyltrimethysilane 13 catalyzed by Lewis acid

Table 10 .
Nucleophilic allylic substitution catalyzed by transition metal

Table 11 .
Catalytic alkylation of furan 7l catalyzed by Lewis acid In 2013, Ramasastry et al.Reported C-C, C-N, C-O and C-S bond forming reactions of furfuryl cations with different nucleophiles catalyzed by BiCl 3

Table 12 .
Nucleophilic substitution of tertiary alcohols 14 catalyzed by Lewis acid

Table 13 .
Nucleophilic substitution of allylic alcohols 20 catalyzed by Lewis acid

Table 14 .
Nucleophilic substitution of alcohols catalyzed by Lewis acid

Table 15 .
Nucleophilic substitution of alcohols 6 and 20 catalyzed by Lewis acid

Table 16 .
Direct catalytic substitution of secondary benzylic alcohol 6a

Table 17 .
Amination of primary alcohols 42 catalyzed by Lewis acid

Table 18 .
Reactions of diphenylmethanol 6b catalyzed by iron catalyst

Table 20 .
Nucleophilic substitution of alcohols catalyzed by iodine Reaction was carried out in the presence of CaSO 4 .b Reaction was carried out in the presence of molecular sieves.c Water (2 equiv.) was added. a

Table 21 .
Nucleophilic substitution of alcohols 1 catalyzed by Lewis base catalyst